The primary objective of Project III is to forge new approaches to the surgical management of cutaneous melanoma, by continuing the clinical and translational studies of lymphatic mapping and sentinel node biopsy (SNB) that were developed and initiated under this Program Project. The focal point of Project III is its two Phase III, internatjonal randomized trials of SNB. The first Multicenter Selective Lymphadenectomy Trial (MSLT-I) examines the accuracy and clinical efficacy of SNB as a staging alternative to complete lymphadenectomy (CLND) in patients with clinical stage I melanoma. MSLT-I has completed accrual of 2001 subjects, who are now being followed to determine the long-term survival benefit of immediate CLND for sentinel node (SN) micrometastses versus delayed CLND for nodal recurrence after wide excision alone. Since most patients with micrometastases have no other tumor-involved nodes, CLND may not be necessary in all patients with tumor-involved SN. We are investigating this hypothesis in a second multicenter randomized trial (MSLT-II). Serum and tisue specimens from both trials will be used to evaluate new molecular biomarkers (with Project II) and to investigate histopathologic markers relating to SN tumor burden, architecture and microenvironment (with Project I). These markers should enable us to determine the likelihood of metastasis beyond the SN and thereby identify candidates for CLND and adjuvant therapy. In related Phase l/II trials with Projects I and II, we will continue to study the, biology and pathophysiology of the regional lymphatics and SN, will examine SN immunosuppression as a predisposing factor for establishment of nodal metastasis, and will assess the prognostic relevance of endogenous immune response as a systemic marker of disease status. Thus, the aims are: 1) continue follow-up of subjects in MSLT-I; 2) continue screening, enrollment and randomization in MSLT-II; 3) investigate the biology and pathophysiology of the SN; 4) develop molecular and immunologic markers for detection of occult systemic metastases; and 5) determine the impact of endogenous immune resonse on prognosis and clinical course.